RBC transfusion has long been and currently remains an integral part of the management of sickle cell disease (SCD). The judicious use of blood can be both life-saving and life-prolonging in variety of clinical settings. There are two broad indications for blood transfusion in SCD, maintenance of the oxygen-carrying capacity of the blood and dilution of the circulating HbS-containing cells. The latter may be accomplished both by the direct dilutional effect of transfused blood but also secondarily by suppression of the bone marrow and decreased production of cells capable of sickling. Erythrocyte exchange offers numerous potential advantages over simple transfusion for the management of certain complications of SCD, especially if there is concern of causing circulatory overload or inducing a hyperviscosity state, which may actually exacerbate the propensity to sickle by retarding capillary transit. Guidelines from exchange transfusion therapy should be derived from an understanding of the rheological behavior of sickle cells. Microvascular occlusion by poorly deformable erythrocytes is believed to be the key pathophysiologic event in SCD. We, therefore, investigated the deformability of sickle (SS) cells and their mixture with normal (AA) cells in terms of filterability through nickel mesh. We also examined the role of dense SS cells and dense SS reticulocytes in overall deformability. In this study, we found that the filtration of mixtures of SS and AA erythrocytes was affected in almost linear fashion by both the %SS erythrocytes and %dense cells, and that dense cells impaired the filtration of these mixtures about 25 times as much as the of SS erythrocytes with no dense cells did. Filtration of mixtures of SS cells with no dense cells and AA cells of more than 60% was almost the same as that of normal erythrocytes. These results suggest that exchange transfusion therapy should aim at decreasing dense cells as much s possible, as well as at keeping the level of SS cells to the total cells below 40%. Our results also indicate the possibility that dense SS reticulocytes involved in reduced deformability. Our data, using an automated reticulocyte analyzer, showed that the proportion of high fluorescence-reticulocytes was elevated in the patients with SCD, which indicated the increased regeneration of immature reticulocytes. The benefit of exchange transfusion, therefore, can be not only due to direct dilution effect, but also due to suppression of SS reticulocytes. These studies can provide the practical guideline for exchange transfusion program based on the rheological behavior of sickle cells.